The extrinsic gastrointestinal nervous system plays a key role in the sensing of nutrients and hormones and its translation in terms of control of food intake by the central nervous system. Gut gluconeogenesis is a new function with benefits in energy homeostasis. The sensing of gut-released glucose by gastrointestinal nerves in post-absorptive periods may have a role for example in the metabolic benefits of gastric bypass surgeries of obesity (1). Regarding major macronutrients as glucose and protein, they are sensed by the gastrointestinal neural system and the transmission of the signals to the brain promotes satiety phenomena. Glucose is sensed in the portal vein by neurons expressing the glucose receptor SGLT3 and activates the main regions of the brain involved in the control of food intake (2,3). Protein indirectly act on food intake by inducing intestinal gluconeogenesis and the sensing of released glucose by the portal glucose sensor (4,5). Similarly, soluble fibers and their products (short-chain fatty acids) mediate their anti-obesity and anti-diabetic benefits via a reflex arc with the brain inducing intestinal gluconeogenesis (6). This new knowledge provides novel mechanisms of control of body weight, which might be useful to envision future approaches of prevention or treatment of obesity and diabetes.